Production of CCL 20 from lung cancer cells induces the cell migration and proliferation through PI 3K pathway
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Abstract Tumour inflammatory microenvironment is considered to play a role in the sensitivity of tumour cells to therapies and prognosis of patients with lung cancer. The expression of CCL 20, one of the critical chemoattractants responsible for inflammation cells recruitment, has been shown overexpressed in variety of tumours. This study aimed at investigating potential mechanisms of CCL 20 function and production in human non‐small cell lung cancer ( NSCLC ). Expression of CCL 20 gene and protein in lung tissues of patients with NSCLC and NSCLC cells (A549) were determined. The interleukin ( IL )‐1β‐induced signal pathways in A549 and the effect of CCL 20‐induced A549 cell migration and proliferation were determined using migration assays and cell‐alive monitoring system. Mechanisms of signal pathways involved in the migration of CCL 20 were also studied. We initially found that NSCLC tumour tissues markedly overexpressed CCL 20 in comparison with normal lung samples. In addition, IL ‐1β could directly promote CCL 20 production in lung cancer cells, which was inhibited by extracellular signal‐regulated kinase (ERK)1/2 inhibitor, p38 mitogen‐activated protein kinase (p38 MARP) inhibitor or PI 3K inhibitors. CCL 20 promoted lung cancer cells migration and proliferation in an autocrine manner via activation of ERK 1/2‐ MAPK and PI 3K pathways. Our data indicated that IL ‐1β could stimulate CCL 20 production from lung cancer cells through the activation of MAPK s and PI 3K signal pathways, and the auto‐secretion of CCL 20 could promote lung cancer cell migration and proliferation through the activation of ERK and PI 3K signal pathways. Our results may provide a novel evidence that CCL 20 could be a new therapeutic target for lung cancer.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, exposure to it eliciting a broad spectrum of deleterious pathophysiological effects. Since mitogen-activated protein kinase (MAPK) pathways appear to play an important role in both cell survival and the apoptotic process, we assessed the effects of TCDD on the activation of extracellular signal-regulated kinase (ERK), Jun-N-terminal kinase (JNK), p38 MAPKs and caspase-3 in RAW 264.7 cells. TCDD treatment induced a transient upshift in ERK activity, followed by a decline, but a concomitant dramatic activation of p38. However, TCDD did not cause any apparent change in the activity of JNK, though it induced an up-regulation in caspase-3 activity. These results demonstrate that the equilibrium between the ERK and p38 pathways is critical to the fate of the cells, and that the activation of p38, upstream of caspase, plays an important role in the apoptotic process. The data obtained in this study also suggests that TCDD activates the MAPK pathway via an arylhydrocarbon receptor (AhR)-independent mechanism in RAW 264.7 murine macrophages.
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Autocrine regulation is defined as a mechanism of self-control in growth and differentiation; this mode of regulation among histologically homologous cells is mediated humorally. Autocrine mechanisms involve: 1. Autonomously controlled production and secretion of autocrine mediators. 2. Distribution of autocrine mediators among cells. 3. Expression by cells of functional receptors for autocrine mediators. 4. Transduction and intracellular integration of signals mediated by autocrine mediators. 5. Growth response. 6. Maintenance of autonomous control of growth and/or differentiation state in the progeny Biochemical and biological evidence for most of these steps in various transformed cells makes it possible to analyze autocrine control as a multifaceted process. This process depends on tumor cellularity and histoarchitecture, on time and on external influences on secretion of autocrine mediators (e.g., estrogens in estrogen-dependent breast cancer). We review the quantitative aspects of experimental evidence for autocrine control in tumors and examine the phenomenological and some mechanistic concepts in creating integrative, quantitative, and experimentally verifiable mathematical models of autocrine regulation.
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AIM: To investigate the key molecular mechanism of inflammatory response in alveolar epithelial cells induced by nontypeable haemophilus influenzae(NTHi).METHODS: A549 cells were co-cultured with NTHi(multiplicity of infection,MOI: 10) and harvested 15 min and 30 min after stimulation.The phosphorylation of p38 mitogen activated protein kinase(p38 MAPK) in A549 cells was detected by Western blotting.The intracellular expression of nuclear factor-κB(NF-κB) p65 was examined by flow cytometry 4 h after stimulation.A549 cells were preincubated with p38 inhibitor(SB203580) or NF-κB inhibitor(PDTC) for 1 h and then stimulated with NTHi for 24 h.The level of interleukin 8(IL-8) in the supernatants was determined by enzyme-linked immunosorbent assay(ELISA).RESULTS: The phosphorylation of p38 MAPK was rapidly induced by NTHi stimulation.The expression of NF-κB p65 in A549 cells after NTHi stimulation was significantly up-regulated compared with control group(P0.05).The level of IL-8 in the supernatants was increased 24 h after bacterial stimulation compared with control group(P0.05).Blockage of p38 MAPK or NF-κB remarkably decreased IL-8 secretion in A549 cells(P0.05).CONCLUSION: NTHi induces inflammatory response in alveolar epithelial cells in a p38 MAPK and NF-κB dependent manner.
Interleukin 8
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Autocrine ligands are important regulators of many normal tissues and have been implicated in a number of disease states, including cancer. However, because by definition autocrine ligands are synthesized, secreted, and bound to cell receptors within an intrinsically self-contained “loop,” standard pharmacological approaches cannot be used to investigate relationships between ligand/receptor binding and consequent cellular responses. We demonstrate here a new approach for measurement of autocrine ligand binding to cells, using a microphysiometer assay originally developed for investigating cell responses to exogenous ligands. This technique permits quantitative measurements of autocrine responses on the time scale of receptor binding and internalization, thus allowing investigation of the role of receptor trafficking and dynamics in cellular responses. We used this technique to investigate autocrine signaling through the epidermal growth factor receptor by transforming growth factor alpha (TGFα) and found that anti-receptor antibodies are far more effective than anti-ligand antibodies in inhibiting autocrine signaling. This result indicates that autocrine-based signals can operate in a spatially restricted, local manner and thus provide cells with information on their local microenvironment.
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Autocrine signaling is defined as the production and secretion of an extracellular mediator by a cell followed by the binding of that mediator to receptors on the same cell to initiate signaling. Autocrine stimulation often operates in autocrine loops, a type of interaction, in which a cell produces a mediator, for which it has receptors, that upon activation promotes expression of the same mediator, allowing the cell to repeatedly autostimulate itself (positive feedback) or balance its expression via regulation of a second factor that provides negative feedback. Autocrine signaling loops with positive or negative feedback are an important feature in cancer, where they enable context-dependent cell signaling in the regulation of growth, survival, and cell motility. A growth factor that is intimately involved in tumor development and progression and often produced by the cancer cells in an autocrine manner is transforming growth factor-β (TGF-β). This review surveys the many observations of autocrine TGF-β signaling in tumor biology, including data from cell culture and animal models as well as from patients. We also provide the reader with a critical discussion on the various experimental approaches employed to identify and prove the involvement of autocrine TGF-β in a given cellular response.
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We have exploited a discrepancy in the oncogenic potential of autocrine and exogenous human growth hormone (hGH) in an attempt to identify molecules that could potentially be involved in oncogenic transformation of the human mammary epithelial cell. Microarray analysis of 19,000 human genes identified a subset of 305 genes in a human mammary carcinoma cell line that were remarkably different in their response to autocrine and exogenous hGH. Autocrine and exogenous hGH also regulated 167 common genes. Semiquantitative reverse transcription-PCR confirmed differential regulation of genes by either autocrine or exogenous hGH. Functional analysis of one of the identified autocrine hGH-regulated genes, TFF3, determined that its expression is sufficient to support anchorage-independent growth of human mammary carcinoma cells. Small interfering RNA-mediated knockdown of TFF3 concordantly abrogated anchorage-independent growth of mammary carcinoma cells and abrogated the ability of autocrine hGH to stimulate oncogenic transformation of immortalized human mammary epithelial cells. Further functional characterization of the identified subset of specifically autocrine hGH regulated genes will delineate additional novel oncogenes for the human mammary epithelial cell.
Neoplastic transformation
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BACKGROUND: The effects of aging on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signaling molecules which may be of particular importance in mediating numerous cellular responses including control of cell growth, differentiation and adaptation are the proteins associated with the mitogen activated protein kinase (MAPK) signaling systems. Further MAPKs have emerged as critical components for regulating numerous mechanotrasductive cellular responses. Previous reports have suggested that agng impairs biaxial-loading induced MAPK phosphorylation. How agigng may affect uniaxial mechanotrasductive processes is not clear. PURPOSE: Here we investigate the ability of a uniaxial stretch activate MAPK pathways in adult (6 mo old), aged (30 mo old) and very aged (36 mo old) Fischer 344 x Brown Norway rats. METHODS: Aortea of adult (6 month), aged (30 month), and very aged (36 month) Fischer 344/NNiaHSD X Brown Norway / BiNia rats were subjected to acute bout of a 20% uniaxial stretch. MAPK protein expression, basal phosphorylation and the uniaxial stretch induced changes in phosphorylation were evaluated by immunoblotting. RESULTS: Western blotting of the MAPK family proteins extracellular signal-regulated kinase (ERK) 1/2, p38-, and c-Jun NH2-terminal kinase (JNK)-MAPKs showed differential expression and basal activation between these proteins with age, with notably higher phosphorylation in ERK1/2 and JNK compared to the 6 month aniumals. However, an acute bout of a 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of ERK 1/2 MAPK, p38-, and JNK MAPK. CONCLUSIONS: These observations confirm previous data demonstrating MAPK proteins are mechanically regulated, and in addition, suggest that MAPK signaling following uniaxial stretch is not altered with aging. Taken together, these data may help explain the age related changes in vascular morphology, function and response to injury. (Supported by funds from NSF Grant #0314742)
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Hematology
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AIM:To investigate the apoptotic effect of cepharanthine(CEP)on neonatal rat cardiomyocytes (NRCMs)and the underlying mechanisms.METHODS:MTT assay was used to detect the viability of the cells.CEP-induced apoptosis in NRCMs was evaluated by Hoechst 33342 staining and the expression of activated caspase-3.The phosphorylation levels of mitogen-activated protein kinases(MAPKs),such as extracellular signal-regulated kinase (ERK),c-jun N-terminal kinase(JNK)and p38 MAPK,were examined by Western blotting.The specific inhibitors of ERK and p38 MAPK were applied for identifying the roles of the corresponding signal pathways in CEP-induced apoptosis of cardiomyocytes.RESULTS:CEP inhibited the viability of NRCMs in a dose-and time-dependent manners.Positive nuclear fragmentation and activated caspase-3 were found in CEP-treated NRCMs.The phosphorylation levels of ERK and p38 MAPK were significantly elevated in CEP-treated NRCMs,but the change of JNK was not obvious.SB203580, an inhibitor of p38 MAPK,significantly alleviated the apoptotic effect induced by CEP.However,PD98059,an inhibitor of ERK1/2,did not significantly reduce the apoptotic effect.CONCLUSION:p38 MAPK is involved in CEP-induced apoptosis in NRCMs.
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